TRPM7 in Synaptic Vesicle Endocytosis and Comparison Between Inhibitory and Excitatory Neurons

Neurons in the brain communicate with each other by signaling molecules called neurotransmitters that are released into the synaptic cleft through synaptic vesicle (SV) exocytosis triggered by an action potential firing. The released neurotransmitter will then bind to the postsynaptic receptors to either activate or inhibit postsynaptic neurons. On the other side, newly formed SVs by endocytosis, after refilled with neurotransmitters, will replenish the readily releasable vesicle pool. Therefore, SV endocytosis is essential to maintain synaptic transmission, during high-frequency stimulations particularly. Upon openings of voltage-gated calcium channels (VGCCs) during AP firings, influx of Ca2+, by binding to synaptotagmins (the Ca2+ sensors for exocytosis), triggers vesicle fusion with the plasma membrane. Meanwhile, it has been shown that Ca2+ is also important in regulating endocytic kinetics of SVs, in addition to exocytosis. However, in contrast to VGCCs as the well-established Ca2+ influx pathway for exocytosis, the identity of the Ca2+ influx pathway for endocytosis remains ambiguous. In the present study, by taking advantage of electrophysiology and live-cell imaging assays, data from my experimental work lead me to propose that a Ca2+-permeable non-selective cation channel TPRM7, a TRP superfamily member, may serve as the Ca2+ influx pathway for SV endocytosis and thus regulate the endocytic kinetics of SVs in neurons. Glutamatergic and GABAergic neurons are the major excitatory and inhibitory neurons in the cerebral cortex, respectively. Studies of the postsynaptic properties of both classes of neurons have been extensively investigated using electrophysiology by taking advantage of the electric responses upon neurotransmitter binding to the postsynaptic receptors. In addition, a growing number of research studies focuses on differences of presynaptic properties in both types of neurons by using electrophysiology and live-cell imaging. However, many critical aspects of SV recycling between excitatory and inhibitory neurons remain to be elucidated. In the current work, using pHluorin-based live-cell imaging assays, we identified that the kinetics of SV exocytosis and endocytosis are different between excitatory and inhibitory neurons. Our work may thus provide important insights to understand the distinct functions of these two types of neurons in the brain.